A hallmark of cancer, i.e., a malignant tumor, is its ability to infiltrate, invade and metastasize to a distant site. It is this ability to develop at a secondary site, discontinuous with the original or primary site, that often results in an extremely poor prognosis and outcome for most cancer patients. It is well known that dissemination of a cancer to secondary sites strongly prejudices the possibility that the patient will be cured of the disease.
Approximately 30% of newly diagnosed patients having a solid tumor will present with some type of metastatic disease, and another 20% will have occult metastases at the time of diagnosis. Currently, radiotherapy and chemotherapy are two important methods used in the treatment of metastatic cancer. Considerable efforts are underway to develop new chemotherapeutic agents to limit and prevent dissemination of cancer to secondary sites.
The use of vanadium compounds and vanadium salts for clinical applications received renewed interest in the late 1970s and early 1980s due to the discovery that vanadate(V) solutions produced insulin-like effects in rat diaphragms and isolated adipocytes in vitro (Tolman et al., Life Sci. 25:1159-1164, 1979; Dubyak et al., J Biol Chem, 255: 5306-5312, 1980; Shechter et al., Nature, 284: 556-558, 1980). Subsequently, the administration of vanadate solutions to diabetic rats was shown to lower blood glucose levels (Heyliger et al., Science, 277: 1474-1477, 1985). Despite a long history of vanadium compounds being used in the treatment of human diseases, however, only a small number of organometallic compounds containing vanadium have been tested for antitumor activity (Morinville et al., Trends Pharmacol. Sci. 19: 452-460, 1998; Kopf-Maier, P, Eur. J Clin Pharmacol, 47: 1-16, 1994; Schwartz M. K., Cancer Res., 35: 3481-3487, 1975; Djordjevic, C., J Inorg Biochem, 25: 51-55, 1985; Djordjevic C., In: H. Sigel and A. Sigel (eds.), Metal ions in biological systems, 31: 595-616, New York: Marcel Dekker, 1995; Schieven et al., J Biol Chem, 270: 20824-20831, 1995; Fature et al., J Cell Biochem, 59: 389-401, 1995); a few of these were shown in the late 1970s and 1980s to possess anticancer activity in vitro as well as in vivo (Kopf-Maier, P, Eur J Clin Pharmacol, 47: 1-16, 1994; Djordjevic C., In: H. Sigel and A. Sigel (eds.), Metal ions in biological systems, 31: 595-616, New York: Marcel Dekker, 1995; Kopf-Maier et al, J Cancer Res Clin Oncol, 102: 21-30, 1981; Kopt-Maier et al., Eur J Cancer, 17: 665-669, 1981; Kopf-Maier et al., J Cancer Res Clin Oncol, 106: 44-52, 1983.
Further, Sakurai, et al., BBRC, Vol. 206, p. 133 (1995) discloses an oxovanadium compound ([VO(Phen)(H2O)2](SO4)) that is active against pharyngonasal cancer as determined by a single assay, and Holmes, Ph.D. Thesis, LSU 1961, and Selbin, Chem. Rev., Vol. 65, p. 155, 1965, disclose oxovanadium compounds [VO(SO4)(Phen)2] and [VO(ClO4)Bpy)2], but do not disclose biological data for the compounds.
Vanadocene dichloride (VDC) has been shown to arrest tumor cell growth (Kopf-Maier, et al., J. Cancer Res. Clin. Onccol., 106: 44-52. 1983), and the oxovanadium compound, [VO(Phen)(H2O)2](SO4), has been shown to be an active pharyngonasal cancer as determined by a single assay (Sakurai, et al, BBRC, 206; 133, 1995). Vanadium compounds have also been shown to induce apoptosis in certain cancer cells (Uckun et al., WO 00/35930).
Against this backdrop the present invention has been developed.